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CAS No. : | 99-59-2 | MDL No. : | MFCD00007261 |
Formula : | C7H8N2O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NIPDVSLAMPAWTP-UHFFFAOYSA-N |
M.W : | 168.15 | Pubchem ID : | 7447 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335-H351-H361 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: With sulfuric acid; sodium nitrite In water at 5℃; Stage #2: With potassium iodide In water at 90℃; for 1 h; |
Step A. 2-Iodo-1-methoxy-4-nitrobenzene 2-Methoxy-5-nitroaniline (10.0 g, 0.060 mol) was stirred in water (150 mL) and concentrated (conc.) sulfuric acid (12 mL, 0.22 mol). The solution was cooled below 5° C. with an ice-salt bath, and a solution of sodium nitrite (4.8 g, 0.070 mol) in water (40 mL) was added dropwise while maintaining the temperature below 5° C. A solution of potassium iodide (16.8 g, 0.101 mol) was added and the mixture was heated to 90° C. for 1 hour. Cooling to 0° C. gave dark red crystals which were filtered, washed with water, and dried. Purification by silica gel chromatography using ethyl acetate/hexanes gave the desired compound (13.6 g, 75percent). 1H NMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.28 (d, 1H), 7.19 (d, 1H), 3.98 (s, 3H). LCMS for C7H7INO3 (M+H)+: m/z=280.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium sulfide; water In methanol; phosphate buffer for 12h; | |
81% | With sulfur; sodium hydroxide In methanol; water at 80℃; for 12h; Green chemistry; | |
24% | With formic acid; triethylamine In acetonitrile for 0.0833333h; Heating; |
8% | With benzophenone; triethylamine In isopropyl alcohol for 3h; Irradiation; | |
With acid bei der elektrolytischen Reduktion an einer Kupferkathode; | ||
With ammonium sulfide | ||
With sodium disulfide | ||
With ethanol; hydrogen sulfide; ammonia | ||
With sodium sulfide; water; sodium hydrogencarbonate | ||
With hydrogenchloride; tin; acetic acid | ||
With ruthenium on carbon; hydrogen at 90℃; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid | ||
With pyridine for 2h; Heating; | ||
With acetic acid In dichloromethane at 20℃; for 90h; | 45 Description 45; N- [2-(Methyloxy)-5-nitrophenyl] acetamide (D45)A mixture of 2-(methyloxy)-5-nitroaniline (3.0 g, 17.8 mmol), acetic anhydride (2.0 g, 1.9 mL, 19.6 mmol), acetic acid (2 mL), toluene (5 mL) and dichloromethane (40 mL) was stirred at room temperature under argon for 90 hours. The reaction was diluted with dichloromethane and saturated sodium bicarbonate solution, and the product extracted into dichloromethane (x2). The combined organic extracts were washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give the title product (D45). MS (ES+) m/e 211 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine at 0 - 20℃; | 98.1 6.73 g 2-Methoxy-5-nitroaniline (40 mmol) was dissolved in 50 ml dry pyridine and cooled to 0° C. 4.16 g methyl chloroformate (44 mmol) was added dropwise and the mixture was stirred at room temperature for additional 2 hours. Then it was evaporated under reduced pressure, 200 ml 0.1 M HCl solution was added and was extracted three times with 50-50 ml ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and evaporated off. Crude product was recrystallized from a minimal amount of acetonitrile to get a light yellow solid. Yield: 5.73 g (63%). Ret. time: 3.24 min., (M+H)-=225. |
48% | With triethylamine In dichloromethane at 20℃; | 27.1 A solution of 2-methoxy-5-nitroaniline (14.4 g, 85 mmol) in CH2CI2 (100 ml_) was treated with CICO2Me (8.0 mL, 103 mmol) and Et3N (17.9 mL, 128 mmol), stirred overnight at 20 0C, and concentrated. Chromatography (20-40% EtOAc/hexanes) provided 27A as a yellow solid (9.21 g, 48%). |
With potassium carbonate; benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sulfuric acid; ethyl acetate; sodium nitrite In water at 50 - 55℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With potassium nitrite; hydrogen iodide; dimethyl sulfoxide In water at 35℃; for 0.166667h; | |
75% | Stage #1: 3-amino-4-methoxynitrobenzene With sulfuric acid; sodium nitrite In water at 5℃; Stage #2: With potassium iodide In water at 90℃; for 1h; | A9.A Step A. 2-Iodo-1-methoxy-4-nitrobenzene 2-Methoxy-5-nitroaniline (10.0 g, 0.060 mol) was stirred in water (150 mL) and concentrated (conc.) sulfuric acid (12 mL, 0.22 mol). The solution was cooled below 5° C. with an ice-salt bath, and a solution of sodium nitrite (4.8 g, 0.070 mol) in water (40 mL) was added dropwise while maintaining the temperature below 5° C. A solution of potassium iodide (16.8 g, 0.101 mol) was added and the mixture was heated to 90° C. for 1 hour. Cooling to 0° C. gave dark red crystals which were filtered, washed with water, and dried. Purification by silica gel chromatography using ethyl acetate/hexanes gave the desired compound (13.6 g, 75%). 1H NMR (300 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.28 (d, 1H), 7.19 (d, 1H), 3.98 (s, 3H). LCMS for C7H7INO3 (M+H)+: m/z=280.1. |
With sulfuric acid; potassium iodide; sodium nitrite 1) water, 0 deg C, 30 min, 2) water, 5 deg C, 2.5 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine 1.) 0 deg C, 30 min, 2.) room temperature, 4 h; | |
96.4% | In pyridine at 20℃; for 2h; | 73.1 Example 73; N-{5-[([4-(Benzhydryloxy)-3-isobutyrylphenyl]amino}carbonyl)amino]-2-methoxyphenyl}methane sulfonamide; (1) N-(2-Methoxy-5-nitrophenyl)methane sulfonamide To a solution (15 ML) of 2-amino-4-nitroanisol (5.00 g, 29.7 mmol) in pyridine was added dropwise methane sulfonylchloride (3.45 ML, 44.6 mmol), and the mixture was stirred at room temperature for 2 hours and was poured into water, to obtain the titled compound as a solid. 7.00 g (96.4%) 1H-NMR (CDCl3) δ; 3.09 (3H, s), 4.03 (3H, s), 6.98 to 7.02 (2H, m), 8.07 (1H, dd, J = 8.8, 2.6 Hz), 8.41 (1H, d, J = 2.6 Hz) |
88% | With pyridine |
71% | With pyridine at 0 - 20℃; for 3h; | 3.A; 7.A A) 2-Methoxy-5-nitro-methanesulfonylaminobenzene.; To a solution of 2-methoxy-5-nitroaniline (5 g) in pyridine (25 ml) at 0°C was added dropwise methanesulfonyl chloride (3.5 ml) then pyridine (0.5 ml). The mixture was left at 0°C for 1 hour, then brought to room temperature for 2 h. The mixture was poured onto ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the solid formed was filtered then washed with water to give 2-Methoxy-5-nitromethanesulfonylaminobenzene (5.2 9,71 %) as an off-white crystalline solid. 'H NMR (CDC13 8.39 (1 H, d, J 2Hz), 8.05 ('H, dd, J 2, 8Hz), 6.99 (1H, d, J 8Hz) and 6.98 (1H, bs, NH), A) 2-Methoxy-5-nitro-methanesulfonylaminobenzene; To a solution of 2-methoxy-5-nitroaniline (5 g) in pyridine (25 ml) at 0°C was added dropwise methanesulfonyl chloride (3.5 ml) then pyridine (0.5 ml). The mixture was left at 0°C for 1 hour, then brought to RT for 2 h. The mixture was poured onto ice (100 g) and dilute hydrochloric acid (3M, 100 ml), the solid formed was filtered then washed with water to give 2-Methoxy-5-nitro-methanesulfonylaminobenzene (5.2 g, 71%) as an off-white crystalline solid. ¹H NMR (CDC13) 8.39 (1H, d, J 2Hz), 8.05 (1H, dd, J 2,8Hz), 6.99 (1H, d, J 8Hz), 6.97 (1H, bs, NH), 4.01 (3H, s) and 3.07 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine In dichloromethane at 0 - 20℃; for 12h; | 41A 2-chloro-N-(2-methoxy-5-nitrophenyl)acetamide To a solution of 2-methoxy-5-nitroaniline (10.00 g, 59.5 mmol) and pyridine (5.1 mL, 62.4 mmol, 1.05 equiv) in CH2CI2 (175 mL) at 0 °C was added chloroacetyl chloride (4.97 mL, 62.4 mmol, 1.05 equiv) dropwise. The resulting mixture was warmed to room temperature, and was stirred at that temperature for 12 h. The resulting solution was concentrated under reduced pressure. The remaining solids were triturated with ethanol, filtered, washed with ethanol, followed by water, followed by ethanol, and dried at 50 °C under reduced pressure to give 2-chloro-N-(2-methoxy-5- nitrophenyl)acetamide (14.1 g, 97%).1H-NM (400 MHz, DMSO-d6): δ [ppm] = 3.98 (s, 3H), 4.41 (s, 2H), 7.27 (d, J=9.1 Hz, 1H), 8.04 (dd, J=2.8, 9.1 Hz, 1H), 8.95 (d, J=2.8 Hz, 1H), 9.85 (s, 1H).LC-MS (Method 3): Rt= 0.95 min; MS (ESIpos): m/z = 245 ([M+H]+, 100%); MS (ESIneg): m/z = 243 ([M-H]-, 100%). |
97% | With pyridine In dichloromethane at 0 - 20℃; for 12h; | Intermediate 26 2-chloro-N-(2-methoxy-5-nitrophenyl)acetamide To a solution of 2-methoxy-5-nitroaniline (10.00 g, 59.5 mmol) and pyridine (5.1 mL, 62.4 mmol, 1.05 equiv) in CH2CI2 (175 mL) at 0 °C was added chloroacetyl chloride (4.97 mL, 62.4 mmol, 1.05 equiv) dropwise. The resulting mixture was warmed to room temperature, and was stirred at that temperature for 12 h. The resulting solution was concentrated under reduced pressure. The remaining solids were triturated with ethanol, filtered, washed with ethanol, followed by water, followed by ethanol, and dried at 50 °C under reduced pressure to give 2-chloro-N-(2-methoxy-5- nitrophenyl)acetamide (14.1 g, 97%). 1H-NM (400 MHz, DMSO-d6): δ [ppm] = 3.98 (s, 3H), 4.41 (s, 2H), 7.27 (d, J=9.1 Hz, 1H), 8.04 (dd, J=2.8, 9.1 Hz, 1H), 8.95 (d, J=2.8 Hz, 1H), 9.85 (s, 1H). LC-MS (Method 3): Rt = 0.95 min; MS (ESIpos): m/z = 245 ([M+H]+, 100%); MS (ESIneg): m/z = 243 ([M-H]-, 100%). |
89.65% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 1h; Inert atmosphere; | 2.3.1 Step 1: Synthetic route for compound C To a solution of compound A (0.50 g, 2.973 mmoles) in ACN (10.0 mL) was added DIPEA (1.57 mL, 8.92 mmoles), followed by dropwise addition of compound B (0.354 mL, 8.920 mmoles) under argon atmosphere. After the addition was complete the reaction was stirred at rt for 1 hour. The completion of the reaction was monitored by TLC. The reactionmixture was concentrated, purified by column chromatography (20 % EtOAc:Hexanes) toisolate the required compound as brown solid (0.653 g, 89.65 %). ‘H-NMR (DMSO-d6, 400MHz) ö 9.90 (s, 1 H), 8.99 (d, J=2.9 Hz, 1 H), 8.07 (dd, J=2.9,9.1 Hz, 1 H), 7.30 (d, J=9.1Hz, 1 H), 4.45 (s, 2 H), 4.01 (s, 3 H). |
In toluene for 3h; Heating; | ||
14.1 g | With pyridine In dichloromethane at 0 - 20℃; for 12h; | 2-chloro-N-(2-methoxy-5-nitrophenyl)aceta To a solution of 2-methoxy-5-nitroaniline (10.0 g, 59.5 mmol) and pyridine (5.1 mL, 62.4 mmol, 1.05 equiv) in DCM (175 mL) at 0 °C was added chloroacetyl chloride (4.97 mL, 62.4 mmol, 1.05 equiv) dropwise. The resulting mixture was warmed to room temperature, and was stirred at that temperature for 12 h. The resulting solution was concentrated under reduced pressure. The remaining solids were triturated with ethanol, filtered, washed with ethanol, followed by water, followed by ethanol, and dried at 50 °C under reduced pressure to give 2-chloro-N-(2-methoxy-5- nitrophenyl)acetamide (14.1 g, 97% of theory). 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.98 (s, 3H), 4.41 (s, 2H), 7.27 (d, J=9.1 Hz, 1H), 8.04 (dd, J=2.8, 9.1 Hz, 1H), 8.95 (d, J=2.8 Hz, 1H), 9.85 (s, 1H). LC-MS (Method 4): Rt = 0.95 min; MS (ESIpos): m/z = 245 ([M+H]+, 100%); MS (ESIneg): m/z = 243 ([M-H]-, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.1% | Stage #1: formic acid With acetic anhydride at 0 - 32℃; for 1h; Stage #2: 3-amino-4-methoxynitrobenzene at 32℃; | 1.B; a Into a 5-L, 3 -neck flask equipped with a mechanical stirrer, a temperature probe and an ice bath was placed, acetic anhydride (367 g, 9.72 mol). Foϖnic acid (367 g, 6.01 mol) was added with stirring and cooling. The rate of addition was such that the temperature did not exceed 32 0C. Stirring was continued for one hour at ambient temperature. Cooling was again applied and 2-methoxy-5-nitroaniline (3) (415 g, 2.47 mol) was added in portions over a 1.5-hour period. The temperature was kept below 32 0C during addition. The thick-yellow slurry was stirred overnight.Water (3 L) was added and the mixture was stirred for an additional 48 hours. The yellow product was collected by filtration and washed with water until the pH of the aqueous washing was neutral. A total of 9.2 L of water was used. The product was dried at 60 0C under house vacuum and afforded 480 g (99.1 %) of the title compound.; As shown in Figure 1, the linear PQQ synthesis began with the addition of commercially available (Aldrich, Milwaukee, WI) 2-methoxy-5-nitroaniline (3) to a cooled solution of acetic anhydride (Ac2O) and formic acid to afford a thick slurry, which was stirred overnight. Water was added to the reaction mixture which was then stirred for an additional two days. The pale product was collected by vacuum filtration and washed with water until the pH of the washing solution was neutral. This first step of the synthesis afforded after drying on the house vacuum, N-(2-methoxy-5-nitrophenyl)formamide (4). |
95% | With formyl acetic anhydride 25 deg C, 10 min; 50 deg C, 20 min; | |
92.5% | With acetic anhydride for 20h; Ambient temperature; |
91% | With (1-methyl-3-(3-sulfopropyl)-1H-imidazol-3-ium)3[PW12O403-] In neat (no solvent) at 70℃; for 1h; Green chemistry; | 4.3 General procedure for the synthesis of formamides (Table 2) General procedure: To a mixture of amine (2 mmol) and formic acid (3 mmol) in a 10 mL round bottomed flask was added [MIMPS]3PW12O40 (140 mg, 0.04 mmol). The reaction mixture was stirred at 70 °C. The progress of the reaction was monitored by TLC. On completion, the mixture was diluted with ethyl acetate (20 mL) with stirring for 30 min. The insoluble catalyst was recovered by filtration. The filtrate was washed with satd solution of NaHCO3 (5 mL×3), brine, and dried over anhyd Na2SO4. The solvent was evaporated and the residue in almost pure form. Recrystallization or column chromatography could be used for further purification. |
91% | With 1-(3-sulfopropyl)pyridinium phosphotungstate at 70℃; for 0.0833333h; | 11 The specific experimental method is as follows: Compound 1 (0.336 g, 2 mmol), formic acid (0.138 g, 0.113 ml, 3 mmol) was added to a 10 ml flask.Group A-F heteropolyacid ionic liquids (0.04 mmol), respectively.The reaction was completed by microwave heating at 70°C for 5 minutes and the reaction was completed. Ethyl acetate 20 ml was added to the reaction mixture.Stir thoroughly for 30 minutes. After filtration, the filtrate was evaporated to dryness and compound 2 was obtained after recrystallization. |
In acetic anhydride | Reference Example. Preparation of PQQ disodium salt Reference Example. Preparation of PQQ disodium salt (0106) PQQ disodium salt was obtained by the following operations: Based on the chemical synthesis process reported by Corey, et al, in a literature published in 1981 (J. Am. Chem. Soc., 1981, 103, 5599-5600), the synthetic process routes and conditions were modified by optimization, and PQQ disodium salt was obtained after nine-step reactions. Compared with the literature of Corey, the optimization and modification in the method of the invention were reflected in the following aspects: 1) noble metal platinum, which was used as a catalyst in the catalytic hydrogenation in the literature, was replaced with palladium; 2) methyl 2-methylacetylacetate, which was used as a coupling agent in the diazotization coupling reaction in the literature, was replaced with ethyl 2-methylacetylacetate; and, 3) the ester hydrolyzation in the literature, wherein the ester reacted with an orthoformate first to produce a monoketal which was then hydrolyzed to obtain the final product under alkaline conditions, was changed into direct hydrolyzation under alkaline conditions followed by pH adjustment to obtain the product. (0107) The specific synthetic procedure was as follows: (1) Formylation reaction: the amino group in the raw material, 2-methoxyl-5-nitroaniline, was protected by formylation under the action of formic acid and acetic anhydride to obtain N-(2-methoxyl-5-nitrophenyl) formamide; (2) Catalytic hydrogenation reaction: with ethanol as the solvent and palladium/carbon as the catalyst, the nitro group on the aromatic ring of the compound in which the amino group was protected by formylation was reduced into amino group to obtain N-(5-amino-2-methoxylphenyl)formamide; (3) Diazotization coupling reaction: under the action of sodium nitrite, the amino group was diazotized to form diazonium fluoroborate which coupled with ethyl 2-methylacetylacetate directly to obtain ethyl 2-[(3-formamido-4-methoxyl)aryl] hydrazono}-propionate; (4) Reaction for forming pyrrole ring: a pyrrole ring was formed in the product obtained in the preceding step under the action of formic acid to obtain ethyl 6-formamido-5-methoxyl-1H-indole-2-carboxylates; (5) Hydrolyzation reaction of formamide: the amido bond in the formamido group protected in the first step was deprotected under acidic conditions to free the amino group to obtain ethyl 6-amino-5-methoxyl-1H-indole-2-carboxylates; (6) Cyclization reaction: the product with the amino group freed in the preceding step and dimethyl 2-oxo-glutaconate were subjected to cyclization reaction to obtain 9-hydroxyl-5-methoxyl-6,7,8,9-tetrahydro-1H-pyrrolo[2,3-f]quinoline-2,7,9 -tricarboxylic acid-2-ethyl ester-7,9-dimethyl ester; (7) Formation of quinoline ring: a quinoline ring was formed with the product obtained in the preceding step in the presence of cupric acetate under acidic conditions to obtain 5-methoxyl-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid-2-ethyl ester-7,9-dimethyl ester; (8) Oxidation reaction: a quinone ring was formed with the product obtained in the preceding step under the action of an oxidant to obtain 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid-2-ethyl ester-7,9-dimethyl ester; (9) Ester hydrolyzation reaction: the three ester groups in the PQQ ester were hydrolyzed under alkaline conditions; after hydrolyzation, pH of the solution was adjusted to 3.0 using 6 mol/L hydrochloric acid; and after holding for 3 hours, the solid, i.e. PQQ disodium salt, was separated. (0108) The raw PQQ disodium salt was crystalline Form C. (0109) The purity of the PQQ disodium salt was higher than 99.0% as measured by high performance liquid chromatography under the conditions indicated as follows: Instrument model: UlTiMate3000, Dionex, USA Chromatographic column: YMC-C18 250×4.6 mm I.D. Mobile phase: acetonitrile: 100 mM potassium dihydrophosphate = 12 : 88, pH adjusted to 2.0 using phosphoric acid Detection wavelength: 249 nm Column temperature: 35 °C Flowing rate: 1.0 ml/min Injection volume: 10 µl |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With copper diacetate In N,N-dimethyl-formamide at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tert.-butylhydroperoxide; 3 A molecular sieve In dichloromethane for 3.5h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 3-amino-4-methoxynitrobenzene With hydrogenchloride; sodium cyanide In water at -10℃; for 1h; Stage #2: With tin(II) chloride dihdyrate In water at -25℃; for 0.5h; | 13.1 Step 1: Synthesis of (2-methoxy-5-nitrophenyl)hydrazine: Into a 250-mL 3-necked round-bottom flask was placed 2-methoxy-5-nitroaniline (2 g, 11.89 mmol, 1.00 equiv), and hydrogen chloride (16 mL). To this solution was added NaNC (904 mg, 13.10 ramol, 1.10 equiv) at -10 °C, and the resulting mixture was stirred for 1 h. To this solution was added SnCl2-2 H2O (5.45 g, 24.15 mmol, 2.20 equiv) dissolved in HCL The resulting solution was stirred for 30 rain at -25 °C, The solids were collected by filtration. The solids of the solution were dissolved in potassium hydroxide (25%). This resulted in 1.3 g (60%) of the title compound as a red solid. LC-MS: (ES, m/z): RT = 0.34 min, LCMS45: m/z = 184.07 [M+l]. 1HNMR (400 MHz, DMSO-d6) δ 7,79 (d, J= 2.9 Hz, IH), 7,55 (dd, J= 8.8, 2.9 Hz, IH), 6.97 (d, J = 8,8 Hz, H i), 6.65 (s, I H), 4.17 (s, 2H), 3.90 (s, 3H). |
With hydrogenchloride; tin(ll) chloride; sodium nitrite 1.) H2O, 10 deg C, 2.) H2O, -20 deg C, 25 min; Yield given. Multistep reaction; | ||
Stage #1: 3-amino-4-methoxynitrobenzene With hydrogenchloride; sodium nitrite Stage #2: With tin(II) chloride dihdyrate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | With pyridine In acetonitrile at 40 - 60℃; | 8.a a) (2-Methoxy-5-nitrophenyl)-phosphoramidic acid diethylester 8,41 g of 2-methoxy-5-nitrophenylamine was suspended in 50 ml of acetonitrile. After addition of 4,84 ml of pyridine 8,67 ml of diethylchlorophosphate, dissolved in 15 ml of acetonitrile, was introduced dropwise. Temperature of the reaction mixture raised to 40°C. After addition of chlorophosphate, temperature was raised to 60°C and kept there until no 2-methoxy-5-nitrophenyl-amine was detectable. Solvent was removed by evaporation and the residue was taken up with water; the undissolved product was isolated by filtration. Yield: 14,04 g (92,3%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 20℃; | 20 Description 20; 4-BrOmO-I-ChIOrO-N- [2-(methyloxy)-5-nitrophenyl] benzenesulfonamide (D20)4-Bromo-2-chlorobenzenesulfonyl chloride (6.96 g, 24.0 mmol) in dichloromethane (50 mL) was added dropwise with stirring to a solution of 2-(methyloxy)-5- nitroaniline (3.36 g, 20.0 mmol) and pyridine (2.37 g, 30.0 mmol) in dichloromethane (25 mL). The reaction mixture was stirred overnight at room temperature and then filtered to afford a batch of the title compound (D20). MS (ES-) m/e 419/421/423 [M- H]. The filtrate was evaporated to dryness and the resulting solid was treated with dichloromethane. The insoluble material was filtered to afford a second batch of the title compound (D20). MS (ES-) m/e 419/421/423 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In dichloromethane at 20℃; | 23 Description 23; 4-BrOmO-N- [2-(methyloxy)-5-nitrophenyl]benzenesulfonamide (D23)4-Bromobenzenesulfonyl chloride (6.13 g, 24.0 mmol) in dichloromethane (35 mL) was added dropwise with stirring to a solution of 2-(methyloxy)-5-nitroaniline (3.36 g, 20.0 mmol) and pyridine (2.37 g, 30.0 mmol) in dichloromethane (65 mL). The reaction mixture was stirred overnight at room temperature and then washed with dil. HCl (3 x 50 mL) followed by brine (1 x 30 mL). It was dried over magnesium sulfate and then evaporated to dryness. This was washed with hexane and the resulting solid was dried in vacuo to afford the title compound (D23). MS (ES-) m/e 385/387 [M-H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; sodium iodide In acetonitrile for 120h; Heating / reflux; | 3.1 A mixture of 2-amino-4-nitroanisole (5.3 g, 31.5 mmol, 1.0 eq.), N,N,N',N'-tetramethyl-1,8-naphthalenediamine (proton sponge: 25.0 g, 116.7 mmol, 3.7 eq.), bromoacetic acid benzyl (20.2 g, 88.3 mmol, 2.8 eq.) and sodium iodide (5.7 g, 37.8 mmol, 1.2 eq.) in acetonitrile (430 mL) was heated to reflux under Ar atmosphere for 5 days. The solvent was evaporated under vacuum. The residue was dissolved in dichloromethane (1L), and the mixture was sequentially washed with water (1L), hydrochloric acid at pH2 (1L x 2), water (1L), aqueous NaHCO3 solution (1L) and with saturated aqueous NaCl solution (300 mL). The obtained organic solution was dried over Na2SO4. The solvent was evaporated under vacuum, and the residue was purified by column chromatography (SiO2, hexane: dichloromethane =1:2-1:10-dichloromethane, v/v) to obtain yellow solids (yield: 52.0%). 1H NMR (300 MHz; CDCl3, r.t., TMS, d/ppm) 3.72 (s, 3 H, ArOCH3), 4.19 (s, 4 H, NCH2), 5.18 (s, 4 H, OCH2 Ar), 6.81 (d, J = 9.3 Hz, 1 H, ArH), 7.30-7.40 (m, 10 H, benzyl ArH), 7.64-7.66 (m, 1 H, ArH), 781-787 (m, 1 H, ArH). ESI-TOFMS (+), m/z: 487.259 [M+Na]+ (calcd. for C25H24N2NaO7+: 487.148), 465.284 [M+H]+ (calcd. for C25 H25 N2 O7+: 465.166). TLC: Rf = 0.5 (Si02, dichloromethane) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 92.5 percent / Ac2O / 20 h / Ambient temperature 2: 80.5 percent / H2 / 5percent Pd/C / dimethylformamide / 3 h / 35 °C / 1500.1 Torr | ||
Multi-step reaction with 2 steps 1: 95 percent / formic-acetic anhydride / 25 deg C, 10 min; 50 deg C, 20 min 2: 93 percent / H2 / Adams platinum catalyst / ethanol / 65 °C | ||
Multi-step reaction with 2 steps 1: 1-(3-sulfopropyl)pyridinium phosphotungstate / 0.08 h / 70 °C 2: sodium tetrahydroborate / N,N-dimethyl-formamide / 120 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate In chlorobenzene for 48h; Heating / reflux; | 3 A mixture of 2-methoxy-5-nitro-phenylamine (16.8g, 0.1mol), bis-(2-chloro-ethyl)-amine hydrochloride (17. 8g, 0.1mol) and potassium carbonate (69g, 0.5mol) in chlorobenzene (300 ml) was refluxed for 48h, washed by water. The water phase was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, purified with flash chromatography on silica gel (CH2Cl2/MeOH) to give the desired product, 1-(2-methoxy-5-nitrophenyl)piperazine (10.7g, 45%). 1H NMR (400 MHz, CDCl3) : δ (ppm) 7.95 (dd, 1H), 7.79 (d, 1H), 6.90 (d, 1H), 3.98 (s, 3H), 3.09 (s, 8H), 1.96 (s, 1H). MS (APCI) : m/z 238 (MH+ ; 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In water at 20℃; for 1.5h; | 13 2-Methoxy-5-nitroacetanilide To a stirred solution of 90 g (0.54 mol) of 2-methoxy-5-nitroaniline in 1100 mL of water was slowly added acetic acid (200 mL, 2.12 mol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hour, and subsequently filtered. The solid was washed with water, ether, and dried to give 133 g of crude yellow product (90% yield), mp 172-177°C;1H NMR (DMSO-d6) δ 9.56 (s, 1H), 9.00 (d, J = 3 Hz, 1H), 8.02 (dd, J = 3 Hz, 9 Hz, 1H), 7.26 (d, J = 9 Hz, 1H), 3.99 (s, 3H), 2.15 (s, 3H); MS (ES) m/z 211.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With acetic acid In water | 13 2-Methoxy-5-nitroacetanilide EXAMPLE 13 2-Methoxy-5-nitroacetanilide To a stirred solution of 90 g (0.54 mol) of 2-methoxy-5-nitroaniline in 1100 mL of water was slowly added acetic acid (200 mL, 2.12 mol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hour, and subsequently filtered. The solid was washed with water, ether, and dried to give 133 g of crude yellow product (90% yield), nip 172-177° C.; 1H NMR (DMSO-d6) δ 9.56 (s,111), 9.00 (d, J=3 Hz, 1H), 8.02 (dd, J=3 Hz, 9 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 3.99 (s, 3H), 2.15 (s, 3H); MS (ES) m/z 211.1 (M+1). |
90% | With acetic acid In water | R.50 N-(2-Methoxy-5-nitrophenyl) acetamide REFERENCE EXAMPLE 50 N-(2-Methoxy-5-nitrophenyl) acetamide To a stirred solution of 90 g (0.54 mol) of 2-methoxy-5-nitroaniline in 1100 mL of water was slowly added acetic acid (200 mL, 2.12 mol) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and filtered. The solid was washed with water, ether, and dried to give 133 g of crude yellow product (90% yield), mp 172-177° C.; 1H NMR (DMSO-d6) δ 9.56 (s, 1H), 9.00 (d, J=3 Hz, 1H), 8.02 (dd, J=9 Hz, 3 Hz, 1H), 7.26 (d, J=9 Hz, 1H), 3.99 (s, 3H), 2.15 (s, 3H); MS (ES) mlz 211.1 (M+1). |
592.3 g (93.6%) | With acetic anhydride; acetic acid In water | 1.a a a 2-Acetylamino-4-nitro-1-methoxybenzene 504 g (3 mol) of 2-amino-4-nitro-1-methoxybenzene are introduced into 860 ml of acetic acid and 600 ml of water (or the combined main filtrate and first wash filtrate of a previous batch) and the mixture is heated to 80° C. 358 g (3.2 mol) of acetic anhydride are added dropwise in the course of 10 minutes. The mixture is subsequently stirred at 80° C. for 4 hours, and then cooled to room temperature, while stirring, by removing the heating bath and finally to 15° C. The pale yellow needles which have precipitated are filtered off with suction, washed with 300 ml of 60% strength acetic acid and 1500 ml of water in several portions and dried. Yield: 592.3 g (93.6%) Melting point: 174°-175° C. Uniform according to chromatographic analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With isopentyl nitrite In acetonitrile at 45℃; for 1h; | 28.1 A solution of 2-methoxy-5-nitroaniline (10.8 g, 64 mmol) and DMS (10.6 mL, 96 mmol) in CH3CN (100 mL) was treated slowly with isoamyl nitrite (10.3 mL, 77 mmol) and then heated at 45°C for 1 h. The reaction was concentrated and subjected to chromatography (10% EtOAc/hexanes) to provide 28A (9.1 g, 71 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 169; 2 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 169 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at O0- 50C was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9: 1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 169 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at O0- 50C was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9: 1 ) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%).To a stirred solution of 1 1.2 g (50.0 mmol) of (2) in 150 mL of anhydrous THF at O0C under the nitrogen, was added 3.Og (75mmol) of NaH (60% in oil). The suspension was stirred for 0.5h at O0C and 1 OmL (150mmol) of iodomethane was added at O0C. After the mixture warmed to room temperature and stirred for 3h, the reaction was quenched by ice brine and extracted with EtOAc(20OmL). The organic phase was washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and the solid was washed with hexane/EtOAc (9: 1) to give pure product N-(2-Methoxy-5-nitro- phenyl)-N-methyl-propionamide (3) as a light yellow solid (1 1.3 g, 95% yield).N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) (10. Og 42mmol ) and borane- methyl sulfide complex (21 mL of 2.0M solution in tetrahydrofurane) in 50 mL THF were heated unter reflux for 30 min, cooled and quenched by ice- water (slowly). Extraction with EtOAc and the EPO organic layer washed with brine dried (Na2SO4), filtered and evaporated in vacuo to give (9.1 g, 96% ) (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) as a yellow oil.A solution of 9.0 g (40.1mmol mmol) of (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) in 200 mL of MeOH/EtOAc (1 :1) containing 5% w/w of Pd-C (10%) was subjected to hydrogenation (1 atm, balloon) overnight. The contents of the flask were passed through a short pad of celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give 7.7 g (92%) of crude amine 4-Methoxy-N3-methyl-N3-propyl-benzene-l,3-diamine (5) of an oil.To a stirred solution of 6.8 g (35.0 mmol) of (5) in 150 mL Of CH2Cl2 at RT was added 6.4g (35mmol) of l,l '-thiocarbonyldiimidazole. The mixture was stirred at room temperature for 15 minutes and then evaporated under reduced pressure and the residue was passed through a short pad of silica gel, eluting with a gradient of hexane/EtOAc, which gave (5-Isothiocyanato-2-methoxy- phenyl)-methyl-propyl-amine (6) (7.85g, 95%) as a colorless oil.To a stirred solution of 4.5g (19.0mmol) of the isothiocyanate (6) in 6OmL of ethanol was added 4.0 g (19.0mmol) of the hydrazide (7) portion wise. The resultant mixture was then heated at 70 0C for 1 h, then cooled. Solvent was removed on rotary evaporator and the residue was treated with hexane/EtoAc (9: 1). The white precipitate thus obtained was filtered, washed with ether (2 X 50 mL) and vacuum dried to 7.6 g (90%) of (8) as white solid.To a solution of 1.36 g (34mmol) of NaOH in 80 mL of water was added 7.5g (16.8mmol) of the intermediate (8) portion-wise. After the dissolution of the solid (1 -2 min), the flask was flushed with nitrogen and heated to 1 10 0C for 3h. The reaction mixture was cooled, an additional100 mL of water was added and the whole mixture was acidified with cone. HCI to pH 7. The white precipitate thus obtained was filtered, washed with water (3 X 75 mL) and dried. The crude product was then re-dissolved in a mixture of 200 mL of ethyl acetate, dried over anhydrous Na2SO4 and passed through a'short pad of silica gel with an additional 150 mL of ethyl acetate as eluent. The filtrates were concentrated and crude product was re-precipitated in 3: 1 hexane/ethyl acetate to give6.83 g (95%) of 4-isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H- [l ,2,4]triazol-3-yl} -benzene- 1, 3 -diol as white solid.1H NMR (300 MHz, DMSO-d6), (ppm): 9.58 (s, IH); 9.39 (s, I H); 6.92- 6.83 (m, 3H); 6.56(d, J=I .8 Hz, I H); 6.23 (s, I H); 3.74 (s, 3H); 3.0-2.93(m, IH); 2.81 (t, J=6.9 Hz, 2H); 2.48(s, 3H); 1.31 -1.24 (m, 2H); 0.96 (d, J= 6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H);ESMS clcd for C22H28N4O3S: 428.19; Found: 429.2 (M+H)+. |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 2 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 169 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0°-5° C. was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7 g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 169 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at O0- 50C was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2-Methoxy- 5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 169 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at O0- 50C was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7g, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9: 1) to yield solid N-(2-Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
98% | With triethylamine In dichloromethane at 0 - 20℃; for 1.5h; | 2 :2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at O0- 50C was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6Jg, 6.3 mL, 72.0 mmol) for 1 hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2- Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). |
74% | With triethylamine In dichloromethane at 0 - 20℃; | 1 General procedure for the synthesis of 21 4.2.7.1 N-(2-methoxy-5-nitrophenyl)propionamide (19) A total of 2.5 mL (30 mmol) of propionyl chloride was added dropwise to a mixture of 5.0 g of 2-methoxy-5-nitroaniline (18) and 4.3 mL (30 mmol) of TEA in dichloromethane at 0 °C. The mixture was then stirred at room temperature until the starting material was completely disappeared. The solvent was evaporated in vacuo to produce a sticky residue that was extracted with dichloromethane and 0.5 N HCl (25 mL). The organic phase was concentrated, and the solid was purified by column chromatography on silica gel (eluent: petroleum ether:ethyl acetate = 3:1) to yield the desired compound as a white solid (yield: 74%). Mp: 192-193 °C. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.12 (1H, s, NH), 8.51 (1H, s, PhH), 7.72 (1H, d, J = 7.6 Hz, PhH), 7.07 (1H, d, J = 7.6 Hz, PhH), 3.90 (3H,s, OCH3), 2.41 (2H, q, J = 7.6 Hz, CH2), 1.07 (3H, t, J = 7.6 Hz, CH3). ESI-MS (m/z): 225 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.03% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20 - 85℃; for 18h; | A.A49.a Example A49; a) Preparation of intermediate 174; A solution of 2-methoxy-5-nitrobenzenamine (0.0119 mol) and DIPEA (0.0238 mol) in DMF (65 ml) was stirred at r.t. A solution of 2-bromoacetic acid 1,1-dimethylethyl ester (0.0238 mol) in DMF (10 ml) was added dropwise. The reaction mixture was heated to 85 0C for 18 hours. The reaction mixture was poured out into ice water. The product was extracted with EtOAc. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated, yielding 2.1 g (45.03%) of intermediate 174. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 4-aminopyridine In tetrahydrofuran at 25℃; for 3h; | 8 Example 8 2-(4-Iodo-2-methoxy-pyridin-3-yl)-5-methoxy-lH-indol-6-ylamine A solution of 2-methoxy-5-nitroaniline (3.00 g, 17.8 mmol), di-tert-butyl dicarbonate (3.89 g, 17.8 mmol) and pyridine-4-ylamine (1.68 g, 17.8 mmol) in THF (50 mL) was stirred at 25°C for 3 h. The reaction mixture was concentrated in vacuo then diluted with ethyl acetate (50 mL). The organic solution was washed three times with water and once with brine. The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (80/20 hexanes/ethyl acetate) afforded (2- methoxy-5-nitro-phenyl)-carbamic acid tert-butyl ester (3.80g, 79%) as an oil. |
With triethylamine In tetrahydrofuran at 20℃; | B74.A Intermediate B74: λ^-IS-amino^^methyloxyJphenylJ-λ/2,^2- dimethylglycinamide; Step A/Intermediate B75: 1 ,1-dimethylethyl [2-(methyloxy)-5-nitrophenyl]carbamate; To a solution of 2-(methyloxy)-5-nitroaniline (10 g, 60 mmol, Aldrich) in anhydrous THF (300 ml.) was added triethylamine (12.05 g, 120 mmol, Aldrich) and di-tert-butyl dicarbonate (15.6 g, 70 mmol, Aldrich) with catalytic DMAP (~0.100g). After overnight stirring, the reaction was concentrated under reduced pressure, redissolved in ethyl acetate (300 mL), and washed with 10% citric acid (100 mL). The solvent was then removed by rotary evaporation, and the crude 1 ,1-dimethylethyl [2-(methyloxy)-5- nitrophenyl]carbamate placed under high vacuum and used without further purification. ESIMS (M+H)+ = 269. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 3-amino-4-methoxynitrobenzene With tert.-butylnitrite In methanol at 0℃; for 0.5h; Stage #2: acrylic acid methyl ester With methanesulfonic acid; palladium diacetate In methanol at 0 - 25℃; | |
Stage #1: 3-amino-4-methoxynitrobenzene With tetrafluoroboric acid; sodium nitrite Stage #2: acrylic acid methyl ester With 5%-palladium/activated carbon In methanol at 25℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; 3-amino-4-methoxynitrobenzene With acetic acid; sodium sulfate at 25 - 30℃; for 8h; Stage #2: With sodium tris(acetoxy)borohydride at 20 - 25℃; for 3.08333h; Stage #3: With sodium hydroxide In water | 2.I Added 2-methoxy-5-nitro phenylamine (8.0 grams, 47.61 mmol) to a round bottomed flask, followed by the addition of l-boc-4-piperidone (28.42 grams, 142.83 mmol), sodium sulfate (67.6 grams, 476 mmol) and acetic acid (80 mL). The above reaction mass was stirred for 8 hours at ambient temperature. Then added sodium triacetoxyborohydride (30.28 grams, 142.83 mmol) at 20 - 25 0C in 5 minutes and stirred the reaction mass for further 3 hours. The reaction mass was quenched into water (100 mL) and basifed to pH: 9 with 50 % aqueous sodium hydroxide solution. The product was extracted with ethyl acetate (4 x 50 mL). Combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated to obtain oily product. The product was further purified by column chromatography, the eluent being ethyl acetate, n-hexane and triethylamine, to obtain 24.01 grams of pure product.IR spectra (cm"1): 3418, 2950, 1685, 1264, 1172; 1H-NMR (δ ppm): 1.35 - 1.45 (2H, m), 1.47 (9H, s), 2.04 - 2.09 (2H, m), 2.96 - 3.02 (2H, m), 3.50 - 3.52 (IH, m), 3.94 (3H, s), 4.06 - 4.11 (2H, m), 4.33 - 4.35 (IH, d, J = 7.76 Hz), 6.75 - 6.77 (IH, d, J = 8.8 Hz), 7.38 - 7.39 (IH, d, J = 2.64 Hz), 7.60 - 7.63 (IH, dd, J = 8.76, 2.64 Hz);Mass (m/z): 352.2 (M+H)+ | |
Stage #1: N-tert-butyloxycarbonylpiperidin-4-one; 3-amino-4-methoxynitrobenzene With acetic acid; sodium sulfate at 20℃; for 8h; Stage #2: With sodium tris(acetoxy)borohydride at 20 - 25℃; for 3h; Stage #3: With water; sodium hydroxide | 2.I Added 2-methoxy-5-nitro phenylamine (8.0 grams, 47.61 mmol) to a round bottomed flask, followed by the addition of 1-boc-4-piperidone (28.42 grams, 142.83 mmol), sodium sulfate (67.6 grams, 476 mmol) and acetic acid (80 mL). The above reaction mass was stirred for 8 hours at ambient temperature. Then added sodium triacetoxyborohydride (30.28 grams, 142.83 mmol) at 20-25° C. in 5 minutes and stirred the reaction mass for further 3 hours. The reaction mass was quenched into water (100 mL) and basified to pH: 9 with 50% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate (4×50 mL). Combined organic layer was washed with brine (100 mL), dried over sodium sulfate and concentrated to obtain oily product. The product was further purified by column chromatography, the eluent being ethyl acetate, n-hexane and triethylamine, to obtain 24.01 grams of pure product.IR spectra (cm-1): 3418, 2950, 1685, 1264, 1172;1H-NMR (δ ppm): 1.35-1.45 (2H, m), 1.47 (9H, s), 2.04-2.09 (2H, m), 2.96-3.02 (2H, m), 3.50-3.52 (1H, m), 3.94 (3H, s), 4.06-4.11 (2H, m), 4.33-4.35 (1H, d, J=7.76 Hz), 6.75-6.77 (1H, d, J=8.8 Hz), 7.38-7.39 (1H, d, J=2.64 Hz), 7.60-7.63 (1H, dd, J=8.76, 2.64 Hz);Mass (m/z): 352.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 3-amino-4-methoxynitrobenzene With tert.-butylnitrite In methanol at 0℃; for 0.5h; Stage #2: acrylic acid n-butyl ester With methanesulfonic acid; palladium diacetate In methanol at 0 - 25℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate In acetonitrile at 150℃; for 0.25h; Microwave irradiation; | General procedure for synthesis of compounds 1, 7-36 General procedure: To a solution of anthranilic acid 2 (0.40 mmol) and Hünig's base (0.60 mmol) in anhydrous acetonitrile (1.0 mL) was added a solution of chloroacetyl chloride (0.44 mmol) in acetonitrile (0.5 mL) at 4 °C. After stirring at r.t. for 2 h, POCl3 (112 µL, 1.2 mmol, 3.0 equiv) was added followed by a solution of aniline (0.60 mmol) in acetonitrile (0.50 mL). The reaction mixture was heated in a microwave reactor at 150 °C for 15 min, cooled to r.t. and treated with K2CO3 (300 mg) and EtOH (1.0 mL). The mixture was heated at 150 °C for 5 min in the microwave reactor. To this mixture, a solution of piperazine, morpholine, or piperidine (0.44 mmol) in EtOH (0.5 mL) was added. The mixture was heated in the microwave reactor for 10 min at 150 °C and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With toluene-4-sulfonic acid at 120℃; for 20h; Inert atmosphere; | |
14% | With toluene-4-sulfonic acid In isopropyl alcohol at 80℃; for 6h; | 4.3 Step 3: Preparation of 2-((5-chloro-2-((2-methoxy-5-nitrophenyl) amino) pyrimidin-4-yl) amino)-N-methylbenzamide (4); 2-((2,5-dichIoropyrimidin-4-yl)arnino)-N-methylbenzamide (3, 5 g, 16.89 mmol) was taken up in IPA ( 120 mL), 2-methoxy-5-nitroaniline (2.84 g, 16.89 mmol) and p-TSA (3.3 g, 16.89 mmol) to form a mixture and the mixture was stirred at 80 °C for 6 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and filtered through a Buckner funnel. The filtered solid was taken up in ethyl acetate to form a solution, and the solution was successively washed with saturated NaHC03 solution and then water, and then the solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford 2-((5-chloro-2-((2-methoxy-5- nitrophenyl) amino) pyrimidin-4-yl) amino)-N-methyl benzamide as a yellow solid (4, 1 g, 14 %). NMR (DMSO-rf6): δ 8.80-8.70 (d, I H), 8.70-8.60 (d, I H), 8.50 (s, I H), 8.00-7.90 (d, IH), 7.75-7.70 (d, I H), 7.40-7.30 (t, I H), 7.30-7.20 (d, I H), 7.20-7.00 (t, I H), 3.90 (s, 3H), 2.80 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate In <i>tert</i>-butyl alcohol at 85℃; for 14h; | 14.4 Step 4: Synthesis of 2-((5-chloro-2-((2-methoxy-5-nitrophenyl)amino)-7-((2-(trimethyl siIyl)ethoxy)methyl)-7H-pyrroIo[2,3-d]pyrimidin-4-yl)amino)-N-methyIbenzamide (5); 2-((2,5-dichloro-7-((2-(trimethyIsilyl)ethoxy)methyl)-7^methylbenzamide (4, 0.9 g, 1.92 mmol) in t-BuOH (9 mL) was added 2-Methoxy 5-nitro aniline (0.324 g, 1.92 mmol), Pd2(dba)3 (20 mg, 0.019 mmol), X-phos (27 mg, 0.057 mmol), K2C03 (0.529 g, 3.84 mmol) and stirred at 85 °C for 14 h . Reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated, diluted with water, extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. Crude product was purified by columnchromatography using 40% EtOAc-hexane to afford 2-((5-chloro-2-((2-methoxy-5-nitrophenyl)amino)-7- ((2-(trimethylsilyl)ethoxy) methyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl)amino)-N-methylbenzamide (5, 0.531 g, 46%). NMR (400 MHz, CDC13): δ 10.65 (s, I H), 9.73 (s, I H), 8.55-8.52 (d, I H), 7.90-7.85 (dd, I H), 7.59-7.49 (m, 3H), 7.15-7.09 (t, I H), 6.96 (s, I H), 6.93-6.90 (d, IH), 6.20-6.15 (m, IH), 5.60 (s, 2H), 4.03 (s, 3H), 3.70-3.65 (t, 2H), 3.05-3.01 (d, 3H), 0.99-0.95 (t, 2H), -0.93 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With toluene-4-sulfonic acid In isopropyl alcohol at 85℃; for 6h; | 17.4 Step 4: Synthesis of 2-((5-chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl) (methyl)amino)-N-methylbenzamide (5); 2-((2,5-dichloropyrimidin-4-yl) (methyl)amino)-N-methyl benzamide (4, 1.6 g, 5.1 mmol), 2- Methoxy-5-nitro aniline (0.87 g, 5.1 mmol) and p-TSA ( 1 g, 5.1 mmol) were taken in IPA (30 mL) was stirred 85 °C for 6 h. Reaction was monitored by TLC. After completion of reaction, solvent was evaporated to dryness. Reaction mixture was taken in ethyl acetate, washed with water, brined, dried over anhydrous sodium sulfate and evaporated under reduced pressure. Crude product was purified by column chromatography to afford 2-((5-chloro-2-((2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)(methyl)amino)-N-methylbenzamide (5, 0.75 g, 34%) NMR (400 MHz, CDCI3): δ 9.35 (s, I H), 8.18 (s, I H), 8.17-8.15 (d, I H), 8.05 (s, I H), 7.90-7.85 (d, I H), 7.56-7.50 (m, I H), 7.40-7.35 (d, I H), 7.35-7.28 (d, I H), 7.25-7.20 (d, I H), 7.15-7.05 (d, I H), 4.05 (s, 3H), 3.45 (s, 3H), 2.65 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.6% | With potassium carbonate In <i>tert</i>-butyl alcohol at 90℃; for 14h; Inert atmosphere; | 12.3 Step 3: Synthesis of 2-((6-((2-methoxy-5-nitrophenyI)amino)-3-methyl-l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazolo[3,4-d]pyriniidin-4-yl)amino)-N-methylbenzamide (4); 2-((6-chloro-3-methyl- 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazolo[3,4-d]pyrimidin-4-y l)amino)- N-methylbenzamide (3, 0.5 g, 1.25 mmol) was taken in t-butanol ( 10 mL), 2-methoxy-5-nitroaniline (0.21 g, 1.25 mmol), Pd2(dba)3 ( 13 mg, 0.012 mmol), X-phos (0.018 g, 0.037 mmol) and K2C03 (0.33 g, 2.5 mmol) were added and reaction was flushed with nitrogen and stirred at 90 °C for 14 h. Reaction was monitored by LCMS. After completion of the reaction, reacton mixture was concentrated, water was added to it and extraceted with ethyl acetate. Organic layer was dried over anhydrous sodium sulfate and concentrated. Crude product was purified by column chromatography (silica gel; 100% EtOAc) to afford 2-((6-((2-methoxy-5-nitrophenyl) amino)-3-methyl-l -(tetrahydro-2H-pyran-2-yl)-l H-pyrazolo[3,4-d] pyrimidin-4-yl)amino)-N-methyl benzamide (4, 0.15 g, 22.6%). NMR (400 MHz, CDC13): δ 1 1 .00 (s, 1 H), 9.82 (s, 1 H), 8.77-8.73 (d, 1 H), 7.95-7.91 (dd, 1 H), 7.65 (s, 1 H), 7.55-7.51 (m, 2H), 7.18-7.14 (t, 1 H), 6.95-6.92 (d, 1 H), 6.22 (bs, 1 H), 5.98-5.90 (dd, 1 H), 4.22-4.16 (d, 1 H), 4.03 (s, 3H) 3.98-3.93 (t, 1 H), 3.00 (s, 3H), 2.80 (s, 3H), 2.70-2.60 (m, 1 H), 2.0- 1.60 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With hydrogenchloride In ethanol; 2-methoxy-ethanol at 110℃; for 5h; Sealed; | 12.2 Step 2: Synthesis of 27A mixture of 7 (1.42 g, 3.938 mmol, 1 .0 eq), 2-methoxy-5-nitroaniline (927 mg, 5.513 mmol, 1.4 eq), and 2.5 M HCl/EtOH (6 mL) in 35 mL of 2-methoxyethanol was sealed and stirred at 1 10 °C for 5 hrs and cooled to room temperature. The mixture was worked up with sat. Na2C03/DC and purified with isco (MeOH/DCM 1 :20) to give a yellow foam on oil pump, 520 mg, in 27% yield. |
27% | With hydrogenchloride In ethanol; 2-methoxy-ethanol at 110℃; for 5h; Sealed tube; | 12.2 A mixture of 7 (1.42 g, 3.938 mmol, 1.0 eq), 2-methoxy-5-nitroaniline (927 mg, 5.513 mmol, 1.4 eq), and 2.5 M HCI/EtOH (6 mL) in 35 mL of 2-methoxyethanol was sealed and stirred at 110 °C for 5 hrs and cooled to room temperature. The mixture was worked up with sat. Na2C03/DCM and purified with isco (MeOH/DCM 1 :20) to give a yellow foam on oil pump, 520 mg, in 27% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With trifluoroacetic acid In iso-butanol at 100℃; for 18h; | 14.2 Step 2: A solution of 32 (0.82 mmol), 2-methoxy-5-nitroaniline 33 ( l eq) and TFA (3 eq) in 2-BuOH (3 mL) was heated at 100 °C for 18 hrs. Upon cooling EtOAc and aq. NaHC03 were added to the reaction mixture. Extraction (3 x) and concentration of combined extracts gave a solid which was purified on silica gel column (ISCO machine) with 10% MeOH in CH2CI2 as the eluents, furnishing 34 as a brownish solid (55%). |
With trifluoroacetic acid In iso-butanol at 100℃; for 18h; | 14.2 A solution of 32 (0.82 mmol), 2-methoxy-5-nitroaniline 33 (1eq) and TFA (3 eq) in 2- BuOH (3 mL) was heated at 100 °C for 18 hrs. Upon cooling EtOAc and aq. NaHCC were added to the reaction mixture. Extraction (3*) and concentration of combined extracts gave a solid which was purified on silica gel column (ISCO machine) with 10% MeOH in CH2CI2 as the eluents, furnishing 34 as a brownish solid (55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium t-butanolate In toluene; <i>tert</i>-butyl alcohol at 110℃; Inert atmosphere; | 23.4 Step 4: Intermediate 66 (493 mg, 1 mmol), 2-methoxy-5-nitroaniline 33 ( 168 mg, 1 mmol), K2C03 (1.4 mmol), Pd2dba3 (5 mol%) and X-Phos (10 mol%) were weighed into a 100 mL round bottom flask and placed under N2. The solvents toluene ( 10 mL) and tert-b t ol (2 mL) were added as a mixture and the stirring solution was evacuated and backfilled with N2 three times. The resulting mixture was then stirred overnight at 1 10 °C. HPLC showed the reaction to be complete and the solvents were evaporated. The residue was purified by silica column chromatography on ISCO machine (5% MeOH in DCM as eluents) to give coupling product 67 (570 mg, 91 %). |
91% | With tris-(dibenzylideneacetone)dipalladium(0); potassium carbonate; XPhos In toluene; <i>tert</i>-butyl alcohol at 110℃; Inert atmosphere; | 23.4 Intermediate 66 (493 mg, 1 mmol), 2-methoxy-5-nitroaniline 33 (168 mg, 1 mmol), K2CO3 (1.4 mmol), Pd2dba3 (5 mol%) and X-Phos (10 mol%) were weighed into a 100 mL round bottom flask and placed under N2. The solvents toluene (10 mL) and fert-butanol (2 mL) were added as a mixture and the stirring solution was evacuated and backfilled with N2 three times. The resulting mixture was then stirred overnight at 110 °C. HPLC showed the reaction to be complete and the solvents were evaporated. The residue was purified by silica column chromatography on ISCO machine (5% MeOH in DCM as eluents) to give coupling product 67 (570 mg, 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With trifluoroacetic acid In iso-butanol at 120℃; for 24h; Sealed tube; | 7.F 7-((2-methoxy-5-nitrophenyl)amino)4-rnethyl-3-phenyl-3,4- dihyclropyrirniclo [4,5-cl] pyrirnidin4(IH)-one To a solution of I -methyl-7-(methvisulfonyl)3-phenyi-3,4-dihydropyrimido[4,5- d]pyrimidiru2(IH>-one (130 rug, 0.41 mniol) in 2-buthanol (1.0 niL) were added 2-inethoxy- 5-nitroanihine (137 mg, 0.82 mmoi) and TFA (0.1 nI). The reaction mixture was stirred for24 hrs at 120 °Q in sealed reaction vessel, The reaction mixture was cooled to room temperature arid concentrated under reduced pressure. The crude reaction mixture waspartitioned between ethyl acetate (10 mL) and sat. NaHCO3 solution. The water layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, filtered through a pad of cebte and concentrated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (0:100 to 5:95, methanoiIdichioromethane) to give 7-((2-inethoxy-5-nitrophenvi)amino)- I -methyl-3-phenyi- 3,4-dihydropyrimido[4,5-d]pyrimidin-2(i 11)-one (120 rug, 72% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
91% | With toluene-4-sulfonic acid In butan-1-ol at 120℃; Sealed tube; | 1.2 Step 2. 5-chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthyl-2-yl)pyrimidine-2,4-diamine (3) For added sealing tube 2,5-di-chloro-N-(naphthalene-2-yl)pyrimidin-4-amine (2) (3g, 10.3mmol), 2-methoxy-5-nitroaniline (1.91g, 11 . 4mmol), P-toluene sulfonic acid monohydrate (2.95g, 15 . 5mmol), adding butanol (30 ml), sealing, 120 °C stirring overnight. Cooling to room temperature, add 10% NaHCO3aqueous solution, dichloromethane extraction, turned to the almost dry, adding anhydrous ethanol pulping, filtered, dried under vacuum to get the yellow solid (3.96g, yield: 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In iso-butanol at 120℃; Sealed tube; | 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) General procedure: 5-Chloro-N2-(2-methoxy-5-nitrophenyl)-N4-(naphthalen-2-yl)pyrimidine-2,4-di-amine(16) 2,5-Dichloro-N-(naphthalen-2-yl)pyrimidin-4-amine(15) (3 g, 10.3 mmol), 2-Methoxy-5-nitroaniline(1.91 g,11.4 mmol) and p-toluene sulfonic acid monohydrate (2.95 g, 15.5 mmol) were dissolved in 2-butanol(30 ml) heated at 120 °C overnight in seal tube. The mixture solution wasevaporated to dryness, redissolved in DCM (100 ml), washed with saturatedaqueous NaHCO3 and brine, dried with Na2SO4and concentrated. The residue was purified by chromatography to afford thetitle compound (3.96g, 91%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.84 (d, J = 2.8 Hz,1H), 8.27 (s, 2H), 8.21 (s, 1H), 7.95 (dd, J= 8.8 Hz, 2.8 Hz, 1H), 7.83 (d, J = 7.2Hz, 1H), 7.80 (s, 2H), 7.68 (d, J = 8.8Hz, 1H), 7.46-7.39 (m, 2H), 7.23 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H). MS (ESI) m/z 422 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane Inert atmosphere; Reflux; | 6 Wherein intermediate 7 synthetic steps are as follows: The intermediate 6 (870 mg, 3mmol), 2-methoxy-5-nitroaniline (504 mg, 3mmol), palladium acetate (13.5 mg, 0 . 06mmol), 4,5-bis(diphenylphosphino) -9,9-dimethylxanthene (87 mg, 0 . 15mmol), cesium carbonate (1.96g, 6mmol) dissolved in dioxane (20 ml) in, argon replacement three times, heating stir at reflux overnight. Natural return to room temperature, turns on lathe does, adding water (10 ml), dichloromethane extraction three times. Anhydrous Na2SO4drying, turns on lathe does, column chromatography separation to obtain the solid (1.04g, yield: 82%). |
With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium diacetate; potassium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100.0℃; for 5.0h; | 1-(2-Chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde (130 mg, 0.59 mmol) was added to a mixture of 2-methoxy-5-nitroaniline (88.6 mg, 0.53 mmol), Pd(OAc)2 (6.5 mmol, 0.029 mmol), (±)-2,2?-bis(diphenylphosphino)-1,1?-binaphthalene (BINAP, 36.5 mg, 0.059 mmol), K2CO3 (161.8 mg, 1.17 mmol) in 10 mL of 1,4-dioxane (degassed for 20 min prior to use). 1-(2-Chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde was prepared by the known procedure as described in WO 2013/109882 A1. The resulting mixture was stirred at 100 C. for 5 h and then concentrated in vacuo. Cold water was added and the precipitated solid was collected by filtration, washed with DCM (5 mL) and dried to give the desired Intermediate 1 as a yellow solid (0.13 g, 65%); MS (ESI) m/z 355.4 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With hydrogenchloride; acetic acid at 90℃; for 12h; | 8-Methoxy-2-methyl-5-nitroquinoline (3): 5-Nitro-o-anisidine (7.0 g) was taken in a 250 mL RB and a mixed solution of HCl (60 mL) and AcOH (60 mL) was added to it. Next, 7 mL (2.0 equiv.) of crotonaldehyde was added tothe mixture and stirred for 5 mins, till a clear solution being obtained. The mixture was then heated to 90 °C for 12 h. After cooling to room temperature, it was extracted with dichloromethane. Dark DCM layer was discarded and aqueous layer was made to just basic using 10% NaOH solution. This basic solution was then extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4 and evaporated in vacuum. The residue was purified by column chromatography on silica gel using ethyl acetate/ hexanes mixture to afford the desired quinoline. This compound was obtained as yellow powder; yield = (5.6 g/ 7.0 g of 1; 61%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With toluene-4-sulfonic acid In 1,4-dioxane for 8h; Reflux; | 12.4 4th step: 5-chloro-N4-(2-methoxy-4 - (4-methyl piperazin-1-yl) phenyl)-N2-(2-methoxy-5-nitrophenyl) pyrimidine -2,4-diamine (12E) Weighing 2,5-di-chloro-N-(2-methoxy-4 - (4-methyl piperazin-1-yl) phenyl) pyrimidin-4-amine (12D) (0.74g, 2mmol), the 100 ml round-bottom flask. Sequentially adding to the reaction bottle 1,4-dioxane (20 ml), 2-amino-4-nitroanisole (0.41g, 2 . 4mmol) and toluene-P-sulfonic acid (0.76g, 4mmol). The reaction is heated to reflux stirring 8 hours. After cooling to room temperature to be reacted, in the reaction bottle adds by drops full and aqueous solution of sodium bicarbonate (40 ml), the residue is extracted with methylene chloride (100 ml × 2), the combined organic phase with saturated salt water washing (50 ml), anhydrous sodium sulfate for drying, after concentrating under reduced pressure, the residue is separated by silica gel column chromatography (dichloromethane/methanol (v/v) =15:1) to obtain yellow solid title product 5-chloro-N4-(2-methoxy-4 - (4-methyl piperazin-1-yl) phenyl)-N2-(2-methoxy-5-nitrophenyl) pyrimidine -2,4-diamine (12E) (0.7g, yield 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With toluene-4-sulfonic acid In 1,4-dioxane at 100℃; for 8h; | 17.2 2nd step: N4-(2-methoxy-4-morpholinyl-phenyl)-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (17C) Weighing 2-chloro-N-(2-methoxy-4-morpholino-phenyl) pyrimidin-4-amine (17B) (0.48g, 1 . 5mmol) in the 100 ml round-bottom flask. Sequentially added to the reaction bottle 1,4-dioxane (15 ml), 2-amino-4-nitroanisole (0.38g, 2 . 2mmol), P-toluene sulfonic acid monohydrate (0.85g, 4 . 5mmol). The reaction temperature to 100 °C stirring under 8 hours. After cooling to room temperature to be reacted, the reaction bottle to add saturated aqueous solution of sodium bicarbonate (50 ml), the residue with ethyl acetate (100 ml × 2) extraction, combined organic phase with saturated salt water washing (50 ml), dried anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography separation (petroleum ether/ethyl acetate (v/v) =5:1-1:1), the yellow solid obtained N4-(2-methoxy-4-morpholinyl-phenyl)-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (17C) (0.5g, yield 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With toluene-4-sulfonic acid In 1,4-dioxane at 110℃; for 6h; | 5.2 2nd step: N4-[ 2-methoxy-4 - (4-methyl piperazin-1-yl) phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (5C) The 2-chloro-N-[ 2-methoxy-4 - (4-methyl piperazin-1-yl) phenyl] pyrimidin-4-amine (5B) (1.6g, 4 . 8mmol) dissolved in 1,4 dioxane (16 ml) in, adding 2-methoxy-5-nitro-aniline (807 mg, 4 . 8mmol), toluene-P-sulfonic acid (991 mg, 5 . 8mmol), heating to 110 °C reaction 6 hours, saturated sodium bicarbonate aqueous solution is added for pH adjustment system 7-8, dichloromethane (50 ml × 2) extraction, anhydrous sodium sulfate for drying, concentrating under reduced pressure, the residue is purified by silica gel column chromatography (dichloromethane/methanol (v/v) =50:1) to obtain the title product solid bombycinous N4-[ 2-methoxy-4 - (4-methyl piperazin-1-yl) phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (5C) (1.6g, 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | With toluene-4-sulfonic acid In 1,4-dioxane for 24h; Reflux; | 14.2 2nd step: 5-chloro-N4-(2-methoxy-4-morpholino phenyl)-N2-(2-methoxy-5-nitrophenyl) pyrimidine -2,4-diamine (14C) Weighing 2,5-di-chloro-N-(2-methoxy-4-morpholine anilino) pyrimidine -4 amine (14B) (1.06g, 3mmol), the 100 ml round-bottom flask, sequentially adding to the reaction bottle 1,4-dioxane (20 ml), 2-methoxy -5 nitroaniline (0.5g, 3mmol), toluene-P-sulfonic acid (0.68g, 3 . 6mmol), reflux reaction temperature rise, 24 hours later enter the after-treatment. To the reaction flask by adding saturated aqueous solution of sodium bicarbonate (50 ml), the residue with ethyl acetate (100 ml × 2) extraction, the combined organic phase with saturated salt water (30 ml) washing, dry anhydrous sodium sulfate, concentrated under reduced pressure, separating and purifying column chromatography (petroleum ether/ethyl acetate (v/v) =2:1) to obtain yellow solid title product 5-chloro-N4-(2-methoxy-4-morpholino phenyl)-N2-(2-methoxy-5-nitrophenyl) pyrimidine -2,4-diamine (14C) (1.25g, yield 86.8%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With toluene-4-sulfonic acid In 1,4-dioxane at 110℃; for 6h; | 7.2 2nd step: N4-[ 4 - [4 - (cyclopropyl methyl) piperazin-1-yl] - 2-methoxy-phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (7C) The 2-chloro-N-[ 4 - [4 - (cyclopropyl-methyl) piperazine-1-yl-] - 2-methoxy-phenyl]-pyrimidin-4-amine (7B) (1.1g, 3 . 0mmol) dissolved in 1,4 dioxane (16 ml) in, adding 2-methoxy-5-nitro-aniline (504 mg, 3 . 0mmol), toluene-P-sulfonic acid (684 mg, 3 . 6mmol), heating to 110 °C reaction 6 hours, by adding saturated aqueous solution of sodium bicarbonate regulating system pH=7-8, dichloromethane (50 ml × 2) extraction, anhydrous sodium sulfate for drying, concentrating under reduced pressure, the residue is purified by silica gel column chromatography (dichloromethane/methanol (v/v) =50:1) of the obtained solid bombycinous N4-[ 4 - [4 - (cyclopropyl methyl) piperazin-1-yl] - 2-methoxy-phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (7C) (1.6g, yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With toluene-4-sulfonic acid In 1,4-dioxane at 110℃; for 6h; | 8.2 2nd step: N4-[ 4 - [4 - (2-fluoroethyl) piperazin-1-yl] - 2-methoxy-phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (8C) The 2-chloro-N-[ 4 - [4 - (2-fluoroethyl) piperazin-1-yl-] - 2-methoxyphenyl]-pyrimidin-4-amine (8B) (1.6g, 4 . 4mmol) dissolved in 1,4 dioxane (20 ml) in, adding 2-methoxy-5-nitro-aniline (739 mg, 4 . 4mmol), toluene-P-sulfonic acid (1.0g, 5 . 3mmol), heating to 110 °C reaction 6 hours, by adding saturated aqueous solution of sodium bicarbonate regulating system pH=7-8, dichloromethane (100 ml × 2) extraction, anhydrous sodium sulfate for drying, concentrating under reduced pressure, the residue is purified by silica gel column chromatography (dichloromethane/methanol (v/v) =50:1) to obtain the title product solid bombycinous N4-[ 4 - [4 - (2-fluoroethyl) piperazin-1-yl] - 2-methoxy-phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (8C) (1.6g, yield 72%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With toluene-4-sulfonic acid In 1,4-dioxane at 110℃; for 6h; | 9.2 2nd step: N4-[ 4 - [4-acetylprotoaescigenin piperazin-1-yl] - 2-methoxy-phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (9C) The 2-chloro-N-[ 4 - [4-acetyl-piperazin-1-yl-] - 2-methoxy-phenyl] pyrimidin-4-amine (9B) (1.4g, 3 . 9mmol) dissolved in 1,4 dioxane (15 ml) in, adding 2-methoxy-5-nitro-aniline (655 mg, 3 . 9mmol), toluene-P-sulfonic acid (893g, 4.7mmol), heating to 110 °C reaction 6 hours, by adding saturated aqueous solution of sodium bicarbonate system is adjusted to pH 7 to 8, methylene chloride (100 ml × 2) extraction, anhydrous sodium sulfate for drying, after concentrating under reduced pressure, separation and purification with silica gel column chromatography (dichloromethane/methanol (v/v) =50:1) to obtain the title product solid bombycinous N4-[ 4 - [4-acetylprotoaescigenin piperazin-1-yl] - 2-methoxy-phenyl]-N2-(2-methoxy-5-nitro-phenyl) pyrimidine -2,4-diamine (9C) (1.0g, yield 53%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: 3-amino-4-methoxynitrobenzene With hydrogenchloride; sodium nitrite In water at 0 - 5℃; Stage #2: ferrocene With cetyltrimethylammonim bromide In diethyl ether; water at 0 - 5℃; | 2.2 Synthesis of nitrophenylferrocenes 1a-1b General procedure: The synthesis of the nitrophenylferrocenes 1a-1b was accomplished by adopting the method reported previously by our group with some modifications [29]. Nitroanilines (a-b) (100mmol) were added in small portions to 60mL of 18% aqueous hydrochloric acid solution to form a slurry, while maintaining the temperature at 0-5°C using a salt water-ice bath. A solution of sodium nitrite (100mmol) in 25mL of water was introduced dropwise to the slurry. After complete addition, the reaction mixture was stirred for 45min at low temperature (1a-1b as dark red needles (Scheme 1). 2-methoxy-5-nitrophenylferrocene (1a) Quantities used were 16.8g (100mmol) 2-methoxy-5-nitroaniline (a), 6.91g (100mmol) sodium nitrite, 60mL concentrated HCl, 0.5g (1.37mmol) hexadecyltrimethylammonium bromide (CTAB) and 9.2g (50mmol) ferrocene. Yield 68%; Dark red crystals; m.p. 173°C; FT-IR and Raman (powder, cm-1): 3083, 3057 (C-Haromatic), 1595, 1600 (C=C), 1555, 1548 (N-Oasym), 1340, 1344 (N-Osym), 479, 485 (Fe-Cp); 1H NMR (500MHz, DMSO-d6, ppm) δ 8.14 (s, 1H, ArH), 7.84 (d, 1H, J=7.5Hz, ArH), 7.64 (d, 1H, J=8.0Hz, ArH), 4.93 (s, 2H, C5H4), 4.48 (s, 2H, C5H4), 4.12 (s, 5H, C5H5), 3.97 (s, 3H, OCH3); 13C NMR (125.81, DMSO-d6, ppm) δ 148.7, 141.6, 131.8, 130.9, 122.1, 121.4, 86.3, 70.5, 70.1, 67.3; Elemental anal. Calcd. (%) for C17H15FeNO3: C, 60.57; H, 4.46; N, 4.13; Fe, 16.52. Found (%): C, 60.51; H, 4.57; N, 4.04; Fe, 16.63. |
Stage #1: 3-amino-4-methoxynitrobenzene With hydrogenchloride; sodium nitrite In water at 0 - 5℃; for 0.5h; Stage #2: ferrocene With cetyltrimethylammonim bromide In diethyl ether; water |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.7% | With sodium hydroxide; In water;pH 8.0; | 20 g of <strong>[67827-72-9]2-methoxy-5-nitroaniline hydrochloride</strong> (purity 84.3%) was added to a 500 ml beaker,After adding 200 ml of water and stirring, most of the raw materials were dissolved and NaOH was added to adjust the pH of the aqueous phase to 8.Extraction with ethyl acetate three times, the organic phase was extracted with saturated NaCl and dried over anhydrous NaSO4.After filtration and rotary drying, compound 1 was obtained as an orange-red solid 11.6g, yield 83.7% (TLC: PE/EA=5:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With phosphorus trichloride In chlorobenzene at 120℃; for 0.333333h; Microwave irradiation; | 3.1.2. Synthesis General procedure: Cinnamic acid (3.37 mM) was suspended at room temperature in dry chlorobenzene (20 mL) insidea microwave tube, where phosphorus trichloride (1.7 mM) and the corresponding aniline derivative(3.37 mM) were added dropwise. Following this step, a magnetic stirrer was added to the tube and thereaction mixture was transferred to the microwave reactor at 120 C for 20 min, where the synthesis atelevated pressure was performed. After the mixture was cooled to 60 C, the solvent was evaporated invacuum. A solid residue was washed with 2MHCl, and a crude product was recrystallized, using 96%ethanol first, and then using 50% ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.1% | With triethylamine In dichloromethane at 20℃; for 4h; | 26 Example 26 2-(4-fluorophenyl)-N-(2-methoxy-5-nitrophenyl)pyrazolo[1,5-a]pyrimidine-6-amide 0.7mmol 2-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid was dissolved in 5mL thionyl chloride, heated to 80°C and refluxed, and reacted for 6h. The thionyl chloride was distilled off under reduced pressure, and the residue was diluted with 4 mL of anhydrous dichloromethane and prepared into an acid chloride solution for later use. Add 1.05mmol of 2-amino-4-nitroanisole and 0.3mL of triethylamine to the reaction flask, and dissolve it with 6mL of anhydrous dichloromethane. Slowly add the above-prepared acid chloride solution dropwise under ice bath conditions, remove the ice bath after the dropwise addition is complete, and react at room temperature for 4 hours. The reaction solution was quenched with 10 mL of water, washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol, Gradient 0-2%) to obtain 110 mg of light yellow solid with a yield of 44.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 105℃; for 18.5h; | 1a (212 mg, 0.92 mmol) was dissolved in 2-pentanol (3.2 mL). 2-methoxy-5-nitroaniline (155 mg, 0.92 mmol) and paratoluenesulfonic acid monohydrate (351 mg, 1.85 mmol) were added and the mixture was stirred at 105 °C for 18.5 h. The precipitate was filtered and dried in high-vacuum to afford 2a as a paratoluenesulfonic acid salt (318 mg, 95% yield). MS (ESI+): 362.1 1H-NMR (DMSO, 298K, 400MHz): δ (ppm) 2.28, (s, 3H), 4.02 (s, 3H), 7.04-7.12 (m, 2H), 7.23 (t, 1H), 7.39-7.57 (m, 4H), 8.23 (m, 1H), 8.35 (d, 1H), 8.65 (d, 1H), 8.95 (s, 1H), 9.52 (bs, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | at 105℃; for 2.5h; | 1b (250 mg, 1.03 mmol) and 2-methoxy-5-nitroaniline (173 mg, 1.03 mmol) were dissolved in 2-pentanol (5.2 mL). Paratoluenesulfonic acid monohydrate (234 mg, 1.23 mmol) was added and the mixture was stirred at 105 °C for 2.5 h and stirred at RT overnight. The precipitate was filtered, rinsed with 2-pentanol and dried under high-vacuum to give compound 2b as a paratoluenesulfonic salt (328 mg, 85% yield). MS (ESI+): 376.1 1H-NMR (DMSO, 298K, 600MHz): δ (ppm) 3.90 (s, 3H), 4.05 (s, 3H), 7.16 (dd, 1H), 7-26-7.31 (m, 2H), 7.35 (d, 1H), 7.55 (d, 1H), 8.00 (dd, 1H), 8.27 (s, 1H), 8.39 (s, 1H), 8.43 (d, 1H), 9.33 (d, 1H) 13C-NMR (DMSO, 298K, 151MHz): δ (ppm) 33.1 (1C), 56.8 (1C), 108.5 (1C), 110.5 (1C), 110.6 (1C), 112.2 (1C), 114.1 (1C), 118.3 (1C), 121.1 (1C), 121.9 (1C), 122.3 (1C), 125.4 (1C), 129.6 (1C), 133.4 (1C), 137.7 (1C), 140.7 (1C), 153.9 (1C), 157.3 (1C), 159.3 (1C) 162.3 (1C) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.1% | With toluene-4-sulfonic acid In ethanol at 80℃; for 10h; | 1.2 Step 2: 4-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-N-(2-methoxy-5-nitrophenyl)pyrimidine-2-amine (Intermediate C1) 5-(2-chloropyrimidin-4-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (10.0 g, 40.0 mmol),2-methoxy-5-nitroaniline (10.0 g, 60.0 mmol),p-toluenesulfonic acid (3.80 g, 20.0 mmol) was added to ethanol (50 mL),The temperature of the reaction solution was raised to 80°C and the reaction was stirred for 10 hours.After the reaction is completed,Filter while hot,The filter cake was washed with cold ethanol,dry,10.7g of yellow solid was obtained,Yield 70.1%. |
Tags: 99-59-2 synthesis path| 99-59-2 SDS| 99-59-2 COA| 99-59-2 purity| 99-59-2 application| 99-59-2 NMR| 99-59-2 COA| 99-59-2 structure
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